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Synlett 2020; 31(05): 502-506
DOI: 10.1055/s-0039-1691578
DOI: 10.1055/s-0039-1691578
letter
Intramolecular Ring-Opening of Oxetanes: Access to Functionalised Hydroxymethyl 2,3-Dihydroimidazo[1,2-c]quinazolines
Funding sources from AstraZeneca.Further Information
Publication History
Received: 22 October 2019
Accepted after revision: 23 December 2019
Publication Date:
29 January 2020 (online)
![](https://www.thieme-connect.de/media/synlett/202005/lookinside/thumbnails/st-2019-v0577-l_10-1055_s-0039-1691578-1.jpg)
Abstract
An intramolecular oxetane ring-opening was developed, affording novel 2-(hydroxymethyl)-2,3-dihydroimidazo[1,2-c]quinazolines from N-(3-methyloxetan-3-yl)quinazolin-4-amines under mild conditions. The resulting medicinally relevant tricyclic scaffolds were synthesised in good yields with diverse substituents. Moreover, reaction optimisation led to the development of a one-pot procedure.
Key words
oxetane ring-opening - intramolecular cyclization - imidazoquinazolines - one-pot synthesisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1691578.
- Supporting Information
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References and Notes
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- 11 (2-Methyl-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanols 4a–f; General Procedure The appropriate 4-chloroquinazoline 1 (100 mg), 3-methyloxetan-3-amine (2; 1.2 equiv), and DIPEA (2 equiv) were dissolved in MeCN (3 mL) and the solution was sealed in a microwave tube. The tube was purged with N2 for 1 min and then heated to 150 °C for 4 h in a microwave reactor. The mixture was cooled to 25 °C then evaporated to dryness and purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5μ silica, 30 mm diameter, 100 mm long), eluting with decreasingly polar mixtures of 1% aq NH3 and MeCN. Fractions containing the desired compound were evaporated to dryness to afford the product 4. (2-Methyl-9-nitro-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (4b) Yellow solid; yield: 288 mg (93%). 1H NMR (400 MHz, DMSO-d 6): δ = 1.24 (s, 3 H, Me), 3.36 (dd, J = 6.4, 10.9 Hz, 1 H, CH2O), 3.44 (dd, J = 5.9, 10.9 Hz, 1 H, CH2O), 3.77 and 4.15 (d, J = 10.9 Hz, 1 H, and d, J = 10.9 Hz, 1 H, CH2), 5.00 (t, J = 5.9 Hz, 1 H, OH), 7.53 (d, J = 8.9 Hz, 1 H, Ar-H), 8.10 (s, 1 H, Ar-H), 8.32 (dd, J = 2.7, 8.9 Hz, 1 H, Ar-H), 8.56 (d, J = 2.7 Hz, 1 H, Ar-H). 13C NMR (101 MHz, DMSO-d 6, 30 °C): δ = 24.27 (CH3), 53.81 (CH2), 67.66 (CH2O), 71.42 (C), 118.57 (C), 120.54 (CH), 127.07 (CH), 127.93 (CH), 144.18 (C), 147.86 (CH), 150.12 (C), 151.49 (C). HRMS (ESI): m/z [M + H]+ calcd for C12H13N4O3: 261.0909; found: 261.0988, 215.1053 [M – NO2]+.